Kynurenine, a Tryptophan Metabolite That Accumulates With Age, Induces Bone Loss

Abstract

Age-dependent bone loss occurs in humans and in several animal species, including rodents. The underlying causal mechanisms are probably multifactorial, although an age-associated increase in the generation of reactive oxygen species has been frequently implicated. We previously reported that aromatic amino acids function as antioxidants and are anabolic for bone and that they may potentially play a protective role in an aging environment. We hypothesized that upon oxidation the aromatic amino acids would not only lose their anabolic effects but also potentially become a catabolic byproduct. When measured in vivo in C57BL/6 mice, the tryptophan oxidation product and kynurenine precursor, N-formylkynurenine (NFK), was found to increase with age. We tested the direct effects of feeding kynurenine (kyn) on bone mass and also tested the short-term effects of intraperitoneal kyn injection on bone turnover in CD-1 mice. Micro-CT analyses demonstrated kyn-induced bone loss. Levels of serum markers of osteoclastic activity (PYD and RANKL) increased significantly with kyn treatment. In addition, histological and histomorphometric studies showed an increase in osteoclastic activity in the kyn-treated groups in both dietary and injection-based studies. Further, kyn treatment significantly increased bone marrow adiposity, and BMSCs isolated from the kyn-injected mice exhibited decreased mRNA expression of Hdac3, and its co-factor NCoR1 and increased expression of lipid storage genes Cidec and Plin1. A similar pattern of gene expression is observed with aging. In summary, our data show that increasing kyn levels results in accelerated skeletal aging by impairing osteoblastic differentiation and increasing osteoclastic resorption. These data would suggest that kyn could play a role in age-induced bone loss.

Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

“… The hypothetical scheme of central and peripheral kynurenine-dependent regulation on bone remodeling based on our data and the results of other authors (El Refaey et al, 2015 ; Refaey et al, 2017 ). RANKL/OPG, receptor activator of NF-κB ligand/osteoprotegerin axis; Runx2, runt-related transcription factor 2; Hdac3, histone deacetylase-3; ERK, extracellular signal-regulated kinases; AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator protein; CYP1A1, AhR-dependent cytochrome P450 1A1; solid line, activation; dotted line, inhibition.…”

“…We also do not exclude that there are other pathological mechanisms of kynurenine action on bone metabolism (Michalowska et al, 2015 ). In CKD, elevated levels of peripheral kynurenine can affect the RANKL/osteoprotegerin axis and histone deacetylase-3 or runt-related transcription factor 2 expressions (El Refaey et al, 2015 ; Refaey et al, 2017 ). We also do not exclude that this phenomenon was induced by AhR ligands except for kynurenine.…”

“…Authors found the potent inhibition of osteoblastogenesis after blocking of indoleamine 2,3-dioxygenase type 1, the enzyme catalyzing the degradation of TRP in the kynurenine pathway. Recently published data suggest that dietary and intraperitoneally administered kynurenine accelerates age-related bone loss by impairing osteoblastic differentiation and increasing osteoclastic resorption (Refaey et al, 2017 ).…”

Defining osteoblast and adipocyte lineages in the bone marrow

“…These data indicate that the Hdac3 cofactor complex controls energy homeostasis in osteoprogenitors like it does in the liver (28–30). Hdac3 levels decline in human bone with age (24), suggesting a novel potential mechanism that could contribute to marrow fat increases with aging and certain pathologies (i.e., aberrant glucocorticoid signaling, excess oxidized amino acid metabolites), as Hdac3 levels can decrease in these conditions as well (24,31–34). …”

Comparative metabolomics of aging in a long-lived bat: Insights into the physiology of extreme longevity

“…Tumor/pathogen growth proceeds unchecked by the immune system [ 80 ]. In addition, some immune cells instead attack healthy cells of the host and ultimately contribute to age-related and inflammation-related diseases (e.g., sarcopenia, dementia, diabetes; [ 91 ]). As such, the kynurenine pathway is a major focus of immunological research.…”